Vision loss from age-related eye diseases such as age-related macular degeneration, glaucoma, or retinitis pigmentosa is a significant cause of morbidity in elderly Veterans. The cellular, genetic, and molecular homeostatic mechanisms that maintain normal retinal function and the pathomechanisms that compromise retinal function with age are poorly understood. Our long-term objective is to decipher the protective mechanisms required for normal retinal function and to identify pathomechanisms that drive chronic progressive vision loss diseases. A mechanism that we have explored in our VA Merit Award is the role of ER and oxidative stress in progressive vision loss diseases. In particular, we have discovered that impairment of Activating Transcription Factor 6 (ATF6) leads to vision loss in patients. ATF6 is a transcription factor that protects cells from ER and oxidative stress. Recently, we have discovered novel small molecule activators of ATF6 and related ER/oxidative stress regulator genes. Our central hypothesis is that reduction of ER and oxidative stress in the eye through administration of these small molecules will ameliorate chronic progressive retinal diseases arising from ER/oxidative stress. Guided by this hypothesis, we propose the following Specific Aims: 1. Determine the anti-ER stress and anti-oxidant efficacy of novel small molecule ATF6 agonists. In a screen of >500,000 small molecule compounds, we identified several different novel molecules that selectively activate ATF6 in cell culture with no overt toxicity. We have obtained these compounds and will perform quantitative, dose-response pharmacologic experiments to characterize and compare the abilities of these molecules to reduce ER stress, to reduce oxidative stress, and to prevent stress-induced damage and cell death. These studies will reveal if ER and oxidative stress can be prevented by small molecule ATF6 activation. 2. Test if small molecule ATF6 agonist, AA147, prevents retinal degeneration in vivo. We found in vivo intraocular efficacy of a lead small molecule ATF6 agonist, AA147, after intravitreal injection. We will determine the parameters for optimal AA147 efficacy via intravitreal injection. We will perform these studies in a GFP reporter mouse of ER/oxidative stress where GFP intensity corresponds to ER/oxidative stress levels. These studies will reveal if a novel small molecule ATF6 agonist, AA147, can preserve retinal function through its anti-ER/oxidative stress properties in the mouse eye. 3: Characterize the proteostatic properties of novel small molecule XBP1 agonists. XBP1 is a transcription factor that is closely related to ATF6 and shares many transcriptional targets. Our small molecule screen also identified novel agonists for XBP1, and our preliminary data reveals that an XBP1 agonist can robustly remove damaged proteins from cells. We hypothesize that XBP1 agonists will reduce ER stress, oxidative stress, and protein misfolding. We will perform cellular and biochemical studies to characterize the properties of these new XBP1 agonists in retinal assays. These may identify a novel strategy to prevent ER/oxidative stress by XBP1 agonism that complements ATF6 activators. The significance of our studies is that, if successful, we will decipher the role of ER stress regulatory genes in retinal homeostasis and in retinal degeneration. These studies will positively impact patient care by defining new molecular pathways and small molecules that can be further advanced into pharmacologic therapies to prevent vision loss in aging Veterans.